Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Abstract

Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

“…Medullary carcinomas account for Sarcomas demonstrate very specific patterns of genetic aberrations: in fact, the differential diagnosis between various sarcoma subtypes is now almost entirely based on the identification of characteristic gene fusions, or some other peculiar genetic events. Unfortunately, virtually all these sarcoma-specific gene alterations are not druggable, although a few noticeable exceptions exist [58,59]. For example, the majority of gastrointestinal tumors (GISTs) contain imatinib-sensitive mutations either in exons 9, 11, 13 and 17 of the KIT oncogene (approximately 70% of cases), or, significantly less frequently, in exons 12, 14 and 18 of the PDGFRA receptor (<5%) [60,61].…”

The c-Myc/TBX3 Axis Promotes Cellular Transformation of Sarcoma-Initiating Cells

“…Sarcomas comprise a heterogenous group of neoplasms that are derived from mesenchymal tissues such as bone, cartilage, muscle, adipose and fibrous connective tissues. While relatively rare in adults (1% of all cancers), they account for >20% of all pediatric malignancies and in children and young adults they represent some of the most aggressive cancers (1). The clinical management of sarcomas remains uboptimal which is, in part, due to late diagnosis that results from a lack of specific symptoms and frequent misdiagnosis, resistance to current treatment modalities, local recurrence and metastases (1).…”

“…While relatively rare in adults (1% of all cancers), they account for >20% of all pediatric malignancies and in children and young adults they represent some of the most aggressive cancers (1). The clinical management of sarcomas remains uboptimal which is, in part, due to late diagnosis that results from a lack of specific symptoms and frequent misdiagnosis, resistance to current treatment modalities, local recurrence and metastases (1). The cells which give rise to sarcomas are still under debate, but growing evidence suggests that mesenchymal stromal/stem cells (MSCs), and in some instances mesenchymal progenitor cells, may be sarcomainitiating cells (1)(2)(3)(4).…”

“…The clinical management of sarcomas remains uboptimal which is, in part, due to late diagnosis that results from a lack of specific symptoms and frequent misdiagnosis, resistance to current treatment modalities, local recurrence and metastases (1). The cells which give rise to sarcomas are still under debate, but growing evidence suggests that mesenchymal stromal/stem cells (MSCs), and in some instances mesenchymal progenitor cells, may be sarcomainitiating cells (1)(2)(3)(4). However, very little is known about the factors that drive their malignant transformation.…”

A Highly Reliable Convolutional Neural Network Based Soft Tissue Sarcoma Metastasis Detection from Chest X-ray Images: A Retrospective Cohort Study

“…The most common diagnoses in older patients are undifferentiated sarcomas, leiomyosarcomas, liposarcomas, fibrosarcomas and pleomorphic sarcomas [ 4 ]. Based on the histological subtype, the risk of metastasis and the routes it takes are also determined [ 5 ].…”